Antimicrobial lenses, processes to prepare them and methods of their use

ABSTRACT

This invention relates to solutions for packaging ophthalmic devices comprising at least one antimicrobial metal salt which prevent the loss of said antimicrobial metal salt during autoclaving and storage.

RELATED APPLICATIONS

This patent application a continuation-in-part of application Ser. No.10/715,903, filed Nov. 18, 2003.

FIELD OF THE INVENTION

This invention relates to packaging solutions that minimize the loss ofinorganic additives present in a contact lens.

BACKGROUND OF THE INVENTION

Contact lenses have been used commercially to improve vision since the1950s. The first contact lenses were made of hard materials. They wereused by a patient during waking hours and removed for cleaning. Currentdevelopments in the field gave rise to soft contact lenses, which may beworn continuously, for several days or more without removal forcleaning. Although many patients favor these lenses due to theirincreased comfort, these lenses can cause some adverse reactions to theuser. The extended use of the lenses can encourage the buildup ofbacteria or other microbes, particularly, Pseudomonas aeruginosa, on thesurfaces of soft contact lenses. The build-up of bacteria and othermicrobes can cause adverse side effects such as contact lens acute redeye and the like. Contact lenses comprising antimicrobial metal saltshave been disclosed for preventing or retarding bacterial and microbialbuildup. However, for these lenses to be effective commercially, it isnecessary for the amount of antimicrobial metal salt in the lens to beconsistent from lot to lot.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a packaging solution for packaging anophthalmic device comprising at least one antimicrobial metal salthaving a K_(sp) of less than about 10⁻¹⁰ wherein said solution issubstantially free from packaging solution salts which have anions,which when combined with said antimicrobial metal, form a salt having aKSP of less than about 10⁻⁶. When packaged in solutions of the presentinvention, the contact lenses comprising antimicrobial metal saltsmaintain a consistent level of antimicrobial metal salt.

As used herein, the term “ophthalmic device” refers to a device thatresides in or on the eye. These devices can provide optical correction,wound care, drug delivery, diagnostic functionality, cosmeticenhancement or effect or a combination of these properties. The termlens includes but is not limited to soft contact lenses, hard contactlenses, intraocular lenses, overlay lenses, ocular inserts, and opticalinserts and the like.

As used herein, the term, “antimicrobial metal salt” means a salt thatwhen incorporated into an ophthalmic device imparts to the ophthalmicdevice one or more of the following properties, the inhibition of theadhesion of bacteria or other microbes to the device, the inhibition ofthe growth of bacteria or other microbes on the device, and the killingof bacteria or other microbes on the surface of the device or in an areasurrounding the device. For purposes of this invention, adhesion ofbacteria or other microbes to the device, the growth of bacteria orother microbes on the device and the presence of bacteria or othermicrobes on the surface of the device are collectively referred to as“microbial colonization.” Preferably, the lenses exhibit a reduction ofviable bacteria or other microbe of at least about 0.25 log, morepreferably at least about 0.5 log, most preferably at least about 1.0log (≧90% inhibition). Such bacteria or other microbes include but arenot limited to those organisms found in the eye, particularlyPseudomonas aeruginosa, Acanthamoeba species, Staphyloccus aureus, E.coli, Staphyloccus epidermidis, and Serratia marcesens.

As use herein, the term “metal salt” means any molecule having thegeneral formula [M]_(a) [X]_(b) wherein X contains any negativelycharged ion, a is ≧1, b is ≧1 and M is any positively charged metalselected from, but not limited to, the following Al⁺³, Co⁺², Co⁺³, Ca⁺²,Mg⁺², Ni⁺², Ti⁺², Ti⁺³, Ti⁺⁴, V⁺², V⁺³, V⁺⁵, Sr⁺², Fe⁺², Fe⁺³, Ag⁺²,Ag⁺, Au⁺², Au⁺³, Au⁺¹, Pd⁺², Pd⁺⁴, Pt⁺², Pt⁺⁴, Cu⁺¹, Cu⁺², Mn⁺², Mn⁺³,Mn⁺⁴, Zn⁺², and the like. Examples of X include but are not limited toCO₃ ⁻², NO₃ ⁻¹, PO₄ ⁻³, Cl⁻¹, I⁻¹, Br⁻¹, S⁻², O⁻², C₁₋₅alkylCO₂ ⁻¹ andthe like. As used herein the term metal salts does not include zeolites,disclosed in WO03/011351, which is hereby incorporated by reference inits entirety. The preferred a is 1, 2, or 3. The preferred b is 1, 2, or3. The preferred metals ions are Mg⁺², Zn⁺², Cu⁺¹, Cu⁺², Au⁺², Au⁺³,Au⁺¹, Pd⁺², Pd⁺⁴, Pt⁺², Pt⁺⁴, Ag⁺², and Ag⁺¹. The particularly preferredmetal ion is Ag⁺¹. Examples of suitable metal salts include but are notlimited to manganese sulfide, zinc oxide, zinc sulfide, copper sulfide,and copper phosphate. Examples of silver salts include but are notlimited to silver nitrate, silver sulfate, silver iodate, silvercarbonate, silver phosphate, silver sulfide, silver chloride, silverbromide, silver iodide, and silver oxide. The preferred silver salts aresilver iodide, silver chloride, and silver bromide. It is preferred thatthe diameter of the metal salt particles is less than about ten microns(10 μm), more preferably less than about 5 μm, most preferably equal toor less than about 200 nm.

The K_(sp); or solubility product constant is the product of theequilibrium constant K, and the concentration of solid salt in solution.K_(sp) values for a number of salts are published in CRC Handbook ofChemistry and Physics, 78^(th) Edition, CRC Press, Boca Raton Florida,1997-99, pages 8-106 through 8-109). For example, if the metal salt issilver carbonate (Ag₂CO₃), the K_(sp) is expressed by the followingequation

Ag₂CO₃(s)→2Ag⁺(aq)+CO₃ ²⁻(aq)

The K_(sp) is calculated as follows

K_(sp)=[Ag⁺]²[CO₃ ²⁻]

It has been discovered that if a contact lens comprising at least oneantimicrobial metal salt having a K_(sp) of less than about 10⁻¹⁰ ispackaged in a solution which is substantially free from salts havinganions which when combined with said antimicrobial metal form a salthaving a K_(sp) of more than about 10⁻⁶, little of the antimicrobialmetal salt is lost during autoclaving and storing the lens. Preferablythe lenses lose less than about 30% by weight of the antimicrobial saltand preferably less than about 20% by weight during autoclaving andstoring. More preferably, upon repeated autoclaving, at least twoautoclaving cycles, and up to five autoclaving cycles, the loss of theantimicrobial salt is less than about 15%.

Preferably the K_(sp) of the salt formed from said antimicrobial metaland packaging solution salt anion is more than about 10⁻⁶ and the K_(sp)of the antimicrobial metal salt is less than about 10⁻¹². In anotherembodiment, the difference between the K_(sp) of the antimicrobial metalsalt and the salt formed from said antimicrobial metal and the packagingsolution salt anion (or ΔK_(sp)) is at least about six orders ofmagnitude, preferably at least about seven orders of magnitude and morepreferably at least about eight orders of magnitude. Combinations ofantimicrobial metal and packing solutions salts wherein the ΔK_(sp) isless than about 6 orders of magnitude may be used so long as thequantity of the salt in the packing solution is low enough that lossupon repeated autoclaving is less than about 15%.

In one embodiment, the solution may be any water-based solution that isused for the packaging, storage and/or cleaning of contact lenses, solong as the K_(sp) of the salt formed from the antimicrobial metal andthe packaging solution salt anion meets the requirements specifiedherein. Typical solutions include, without limitation, saline solutions,buffered solutions, buffered saline solutions and deionized water. Thepreferred aqueous solution is borate buffered solution containing saltsincluding, without limitation, sodium sulfate, sodium lactate, sodiumcitrate, sodium chloride, mixtures thereof and the like.

In one embodiment of the present invention the packaging solution alsohas an osmolality of about 220 mOsm/kg or greater and preferably ofabout 230 mOsm/kg or greater.

Osmolality is a measure of the number of particles present in solutionand is independent of the size or weight of the particles. It can bemeasured only by use of a property of the solution that is dependentonly on the particle concentration. These properties are collectivelyreferred to as Colligative Properties (vapor pressure depression,freezing point depression, boiling point elevation, osmotic pressure).Osmolality of a solution is the number of osmoles of solute per kilogramof solvent. This is the amount of a substance that yields, in idealsolution, that number of particles (Avogadro's number) that woulddepress the freezing point of the solvent by 1.86K. The osmolalityvalues reported in the Examples were measured via freezing pointdepression using a Micro-Osmometer Model 3 MOplus. Solutions having theosmolility specified herein may be readily prepared by incorporatingappropriate amounts of ionic salts, such as those listed herein. Asuitable concentration range for the salt(s) are between about 0.01 toabout 5 weight % and preferably between about 0.1 to about 3.0 weight %as part of a buffer system (such as borate or phosphate).

In another embodiment the packaging solution also has a conductivity ofat least about 4 mS/cm or greater, and preferably at least about 5 mS/cmor greater. Conductivity is the ability of a material to conductelectric current. Conductivity may be measured using commercialconductivity probes. Solutions having the desired conductivities may bemade by incorporating the salts listed herein. Salts which are moreconductive, such as, for example sodium chloride, may be used in lesserquantities than salts with relatively low conductivities such as sodiumborate.

In a further embodiment solutions of the present invention comprise anosmolality of at least about 220 mOsm/kg and a conductivity of at leastabout 4 mS/cm., preferably an osmolality of at least about 220 mOsm/kgand a conductivity of at least about 5 mS/cm., more preferably anosmolality of at least about 230 mOsm/kg and a conductivity of at leastabout 4 mS/cm., and most preferably an osmolality of at least about 230mOsm/kg and a conductivity of at least about 5 mS/cm.

The solutions of the present invention may also comprise any knownactive and carrier components useful for lens packaging solution.Suitable active ingredients for lens packaging solutions include,without limitation, antibacterial agents, anti-dryness agents, such aspolyvinyl alcohol, polyvinylpyrrolidone, dextran, polyethylene oxides,hydroxy propylmethyl cellulose (HPMC), tonicity agents, pharmaceuticals,nutraceuticals, additives which prevent the lens from sticking to thepackage and the like, and combinations thereof.

To form the solution, the ingredients are combined with the water-basedsolution, stirred, and dissolved. The pH of the solution preferably isadjusted to about 6.2 to about 7.7. The lens to be stored in thepackaging solution of the invention is immersed in the solution and thesolution and lens placed in the package in which the lens is to bestored. Alternatively, the solution may be placed into the package andthe lens then placed into the solution. Typically, the package is thensealed by any convenient method, such as by heat sealing, and undergoesa suitable sterilization procedure.

Soft contact lenses may be made from any hydrophilic hydrogel orsilicone elastomer or hydrogel materials, which include but are notlimited to silicone hydrogels, and fluorohydrogels. Examples of softcontact lenses formulations include but are not limited to theformulations of etafilcon A, genfilcon A, lenefilcon A, polymacon,acquafilcon A, balafilcon A, galyfilcon A, senofilcon A and lotrafilconA, and the like. The preferable contact lens formulations are etafilconA, balafilcon A, acquafilcon A, lotrafilcon A, galyfilcon A, senofilconA and silicone hydrogels, as prepared in U.S. Pat. No. 5,998,498, U.S.Ser. No. 09/532,943, a continuation-in-part of U.S. patent applicationSer. No. 09/532,943, filed on Aug. 30, 2000, WO03/22321, U.S. Pat. No.6,087,415, US 2002/0016383, JP 2001-188181, JP 2001-201723, JP2001-183502, JP 2002-327063, U.S. Pat. No. 5,760,100, U.S. Pat. No.5,776, 999, U.S. Pat. No. 5,789,461, U.S. Pat. No. 5,849,811, and U.S.Pat. No. 5,965,631. These patents as well as all other patent disclosedherein are hereby incorporated by reference in their entirety.

Hard contact lenses are made from polymers that include but are notlimited to polymers of poly(methyl)methacrylate, silicon acrylates,silicone acrylates, fluoroacrylates, fluoroethers, polyacetylenes, andpolyimides, where the preparation of representative examples may befound in U.S. Pat. No. 4,330,383. Intraocular lenses of the inventioncan be formed using known materials. For example, the lenses may be madefrom a rigid material including, without limitation, polymethylmethacrylate, polystyrene, polycarbonate, or the like, and combinationsthereof. Additionally, flexible materials may be used including, withoutlimitation, hydrogels, silicone materials, acrylic materials,fluorocarbon materials and the like, or combinations thereof. Typicalintraocular lenses are described in WO 0026698, WO 0022460, WO 9929750,WO 9927978, WO 0022459, U.S. Pat. Nos. 4,301,012; 4,872,876; 4,863,464;4,725,277 and 4,731,079.

Additionally, suitable contact lenses may be formed from reactionmixtures comprising at least one silicone containing component. Asilicone-containing component is one that contains at least one[—Si—O—Si] group, in a monomer, macromer or prepolymer. Preferably, theSi and attached O are present in the silicone-containing component in anamount greater than 20 weight percent, and more preferably greater than30 weight percent of the total molecular weight of thesilicone-containing component. Useful silicone-containing componentspreferably comprise polymerizable functional groups such as acrylate,methacrylate, acrylamide, methacrylamide, N-vinyl lactam, N-vinylamide,and styryl functional groups. Examples of silicone components which maybe included in the silicone hydrogel formulations include, but are notlimited to silicone macromers, prepolymers and monomers. Examples ofsilicone macromers include, without limitation, polydimethylsiloxanemethacrylated with pendant hydrophilic groups as described in U.S. Pat.Nos. 4,259,467; 4,260,725 and 4,261,875; polydimethylsiloxane macromerswith polymerizable functional group(s) described in U.S. Pat. Nos.4,136,250; 4,153,641; 4,189,546; 4,182,822; 4,343,927; 4,254,248;4,355,147; 4,276,402; 4,327,203; 4,341,889; 4,486,577; 4,605,712;4,543,398; 4,661,575; 4,703,097; 4,837,289; 4,954,586; 4,954,587;5,346,946; 5,358,995; 5,387,632 ; 5,451,617; 5,486,579; 5,962,548;5,981,615; 5,981,675; and 6,039,913; polysiloxane macromersincorporating hydrophilic monomers such as those described in U.S. Pat.Nos. 5,010,141; 5,057,578; 5,314,960; 5,371,147 and 5,336,797; macromerscomprising polydimethylsiloxane blocks and polyether blocks such asthose described in U.S. Pat. Nos. 4,871,785 and 5,034,461, combinationsthereof and the like.

The silicone and/or fluorine containing macromers described in U.S. Pat.Nos. 5,760,100; 5,776,999; 5,789,461; 5,807,944; 5,965,631 and 5,958,440may also be used. Suitable silicone monomers includetris(trimethylsiloxy)silylpropyl methacrylate, hydroxyl functionalsilicone containing monomers, such as3-methacryloxy-2-hydroxypropyloxy)propylbis(trimethylsiloxy)methylsilaneand those disclosed in WO03/22321, and mPDMS containing or the siloxanemonomers described in U.S. Pat. Nos. 4,120,570, 4,139,692, 4,463,149,4,450,264, 4,525,563; 5,998,498; 3,808,178; 4,139,513; 5,070,215;5,710,302; 5,714,557 and 5,908,906.

Additional suitable siloxane containing monomers include, amide analogsof TRIS described in U.S. Pat. No. 4,711,943, vinylcarbamate orcarbonate analogs described in U.S. Pat. No. 5,070,215, and monomerscontained in U.S. Pat. No. 6,020,445, monomethacryloxypropyl terminatedpolydimethylsiloxanes, polydimethylsiloxanes,3-methacryloxypropylbis(trimethylsiloxy)methylsilane,methacryloxypropylpentamethyl disiloxane and combinations thereof.

Suitable hydrophilic components are well known in the art and aredisclosed in WO 2003/022321. Preferred hydrophilic monomers which may beincorporated into the polymer of the present invention includehydrophilic monomers such as N,N-dimethyl acrylamide (DMA),2-hydroxyethyl acrylate, glycerol methacrylate, 2-hydroxyethylmethacrylamide, N-vinylpyrrolidone (NVP), HEMA, and polyethyleneglycolmonomethacrylate. Most preferred hydrophilic monomers include DMA, NVP,HEMA and mixtures thereof.

Polymeric wetting agents and compatibilizing components may also beincluded. As used herein, “polymeric wetting agent” refers to substanceshaving a weight average molecular weight of at least about 2,500Daltons. The preferred weight average molecular weight of thesepolymeric wetting agents is greater than about 100,000; more preferablybetween about 150,000 to about 2,000,000 Daltons, more preferably stillbetween about 300,000 to about 1,800,000 Daltons.

Alternatively, the molecular weight of polymeric wetting agents can bealso expressed by the K-value, based on kinematic viscositymeasurements, as described in Encyclopedia of Polymer Science andEngineering, N-Vinyl Amide Polymers, Second edition, Vol 17, pgs.198-257, John Wiley & Sons Inc. When expressed in this manner,hydrophilic monomers having K-values of greater than about 12 andpreferably between about 30 and about 150.

The way in which the polymeric wetting agent is added to the lens is notcritical. The polymeric wetting agent may be added to the reactionmixture as a polymer, may be formed from at least one hydrophilicmonomer which is added to the reaction mixture and forms a hydrophilicpolymer upon curing of the reaction mixture or may be added after thelens is formed in the packaging solution. Examples of polymeric wettingagents include but are not limited to polymers and copolymers comprisingpolyamides, polylactones, polyimides, polylactams and functionalizedpolyamides, polylactones, polyimides, polylactams, such as DMAfunctionalized by copolymerizing DMA with a lesser molar amount of ahydroxyl-functional monomer such as HEMA, and then reacting the hydroxylgroups of the resulting copolymer with materials containing radicalpolymerizable groups, such as isocyanatoethylmethacrylate ormethacryloyl chloride. Hydrophilic prepolymers made from DMA or n-vinylpyrrolidone with glycidyl methacrylate may also be used. The glycidylmethacrylate ring can be opened to give a diol which may be used inconjunction with other hydrophilic prepolymer in a mixed system toincrease the compatibility of the high molecular weight hydrophilicpolymer, hydroxyl-functionalized silicone containing monomer and anyother groups which impart compatibility. Polymeric wetting agentsinclude but are not limited to those disclosed in U.S. Pat. No.6,367,929, WO 2003/022321 and acyclic polyamides comprising repeatingunits of Formula I

Wherein X is a direct bond,

wherein R³ is a C1 to C3 alkyl group;

-   R¹ is selected from H, straight or branched, substituted or    unsubstituted C1 to C4 alkyl groups,-   R² is selected from H, straight or branched, substituted or    unsubstituted C1 to C4 alkyl groups, amino groups having up to two    carbons, amide groups having up to four carbon atoms and alkoxy    groups having up to two carbons and wherein the number of carbon    atoms in R1 and R2 taken together is 8 or less, and preferably 6 or    less. Homopolymers and copolymers comprising N-vinylpyrrolidone,    N-vinyl-N-methylacetamide, (meth)acrylic acid,    N,N-dimethylacrylamide, combinations thereof and the like are    particularly preferred.

In certain embodiments a hydroxyl containing component may also beincluded. The hydroxyl containing component that may be used to make thepolymers of this invention have at least one polymerizable double bondand at least one hydroxyl group. Examples of polymerizable double bondsinclude acrylic, methacrylic, acrylamido, methacrylamido, fumaric,maleic, styryl, isopropenylphenyl, O-vinylcarbonate, O-vinylcarbamate,allylic, O-vinylacetyl and N-vinyllactam and N-vinylamido double bonds.The hydroxyl containing component may also act as a crosslinking agent.The hydroxyl group may be a primary, secondary or tertiary alcoholgroup, and may be located on an alkyl or aryl group. Examples ofhydroxyl containing monomers that may be used include but are notlimited to 2-hydroxyethyl methacrylate (“HEMA”), 2-hydroxyethylacrylate, 2-hydroxyethyl methacrylamide, 2-hydroxyethyl acrylamide,N-2-hydroxyethyl vinyl carbamate, 2-hydroxyethyl vinyl carbonate,2-hydroxypropyl methacrylate, hydroxyhexyl methacrylate, hydroxyoctylmethacrylate and other hydroxyl functional monomers as disclosed in U.S.Pat. Nos. 5,006,622; 5,070,215; 5,256,751 and 5,311,223. Preferredhydroxyl containing components include 2-hydroxyethyl methacrylate.

In addition, the lens may also include cross-linkers, photoinitiators,UV absorbers, medicinal agents, antimicrobial compounds, reactive tints,pigments, copolymerizable and nonpolymerizable dyes, release agents,combinations thereof and the like. These additional components may beincorporated into the lens in any way, such as, but not limited topolymerized into the lens matrix, admixed into the monomer mix used tomake the lens or absorbed into the lens.

The contact lenses may be coated to increase their compatibility withliving tissue with a number of agents that are used to coat lens. Forexample, the coating procedures, compositions, and methods ofWO03/11551, U.S. Pat. Nos. 6,087,415, 5,779,943, 5,275,838, 4,973,493,5,135,297, 6,193,369, 6,213,604, 6,200,626, and 5,760,100 may be usedand these applications and patents are hereby incorporated by referencefor those procedures, compositions, and methods.

The amount of antimicrobial metal in the lenses is measured based uponthe total weight of the lenses. When the antimicrobial metal is silver,the preferred amount of silver is about 0.00001 weight percent (0.1 ppm)to about 10.0 weight percent, preferably about 0.0001 weight percent (1ppm) to about 1.0 weight percent, most preferably about 0.001 weightpercent (10 ppm) to about 0.1 weight percent, based on the dry weight ofthe lens. With respect to adding metal salts, the molecular weight ofthe metal salts determines the conversion of weight percent of metal ionto metal salt. The preferred amount of silver salt is about 0.00003weight percent (0.3 ppm) to about 30.0 weight percent, preferably about0.0003 weight percent (3 ppm) to about 3.0 weight percent, mostpreferably about 0.003 weight percent (30 ppm) to about 0.3 weightpercent, based on the dry weight of the lens.

The preferred antimicrobial metal salts of this invention are silveriodide, silver chloride and silver bromide, where silver iodide isparticularly preferred.

The term “forming” refers to any of a number of methods used to formlenses that include but are not limited to curing with light or heat.The lens formulations of the present invention can be formed by any ofthe methods know to those skilled in the art, such as shaking orstirring, and used to form polymeric articles or devices by knownmethods.

Metal salts of the invention may be added (prior to curing) to the softcontact lens formulations described in U.S. Pat. No. 5,710,302, WO9421698, EP 406161, JP 2000016905, U.S. Pat. No. 5,998,498, U.S. patentapplication Ser. No. 09/532,943, U.S. Pat. No. 6,087,415, U.S. Pat. No.5,760,100, U.S. Pat. No. 5,776,999, U.S. Pat. No. 5,789,461, U.S. Pat.No. 5,849,811, and U.S. Pat. No. 5,965,631. In addition, metal salts ofthe invention may be added to the formulations of commercial softcontact lenses.

In order to illustrate the invention the following examples areincluded. These examples do not limit the invention. They are meant onlyto suggest a method of practicing the invention. Those knowledgeable incontact lenses as well as other specialties may find other methods ofpracticing the invention. However, those methods are deemed to be withinthe scope of this invention.

The osmolality of a solution may be measured using a Micro-OsmometerModel 3 MOplus and the following procedure. The instrument wasinternally calibrated with NIST traceable 50 mOsm and 850 mOsmstandards. The solutions to be tested were kept sealed in a vial untilevaluation. The sampling system (a pipette fitted with a plunger) wasrinsed by pipetting sample solution into the barrel of the samplingsystem and discarding. Solution was pipetted into the sample system, thesample system was placed in the osmometer and the osmolality wasmeasured. The measurement was repeated three times and the average isreported.

The conductivity may be measured using a FISHER® ACCUMET® 150 and thefollowing procedure. The instrument is calibrated using NIST traceableconductivity standards. The solutions to be tested were kept sealed in avial until evaluation. About 30 ml of solution was placed in a hingedcap sample vial. The conductivity probe is dipped into the solution atleast three times prior to sample evaluation to wet the probe and removeany bubbles. The conductivity probe and automatic temperaturecompensation probe are immersed in the sample solution and theconductivity is recorded when the reading on the instrument stabilizes.

Silver content of the lenses after lens autoclaving was determined byInstrumental Neutron Activation Analysis “INAA”. INAA is a qualitativeand quantitative elemental analysis method based on the artificialinduction of specific radionuclides by irradiation with neutrons in anuclear reactor. Irradiation of the sample is followed by thequantitative measurement of the characteristic gamma rays emitted by thedecaying radionuclides. The gamma rays detected at a particular energyare indicative of a particular radionuclide's presence, allowing for ahigh degree of specificity. Becker, D. A.; Greenberg, R. R.; Stone, S.F. J. Radioanal. Nucl. Chem. 1992, 160(1), 41-53; Becker, D. A.;Anderson, D. L.; Lindstrom, R. M.; Greenberg, R. R.; Garrity, K. M.;Mackey, E. A. J. Radioanal. Nucl. Chem. 1994, 179(1), 149-54. The INAAprocedure used to quantify silver content in contact lens material usesthe following two nuclear reactions:

-   -   1. In the activation reaction, ¹¹⁰Ag is produced from stable        ¹⁰⁹Ag (isotopic abundance=48.16%) after capture of a radioactive        neutron produced in a nuclear reactor.    -   2. In the decay reaction, ¹¹⁰Ag (τ^(1/2)=24.6 seconds) decays        primarily by negatron emission proportional to initial        concentration with an energy characteristic to this        radio-nuclide (657.8 keV).        The gamma-ray emission specific to the decay of ¹¹⁰Ag from        irradiated. standards and samples are measured by gamma-ray        spectroscopy, a well-established pulse-height analysis        technique, yielding a measure of the concentration of the        analyte.

EXAMPLES

The following abbreviations were used in the examples

-   Blue HEMA=the reaction product of reactive blue number 4 and HEMA,    as described in Example 4 or U.S. Pat. No. 5,944,853-   CGI 1850=1:1 (w/w) blend of 1-hydroxycyclohexyl phenyl ketone and    bis(2,6-dimethyoxybenzoyl)-2,4-4-trimethylpentyl phosphine oxide-   DI water=deionized water-   D3O=3,7-dimethyl-3-octanol-   DMA=N,N-dimethylacrylamide-   HEMA=hydroxyethyl methacrylate-   IPA=Isopropyl alcohol-   Macromer=a macromer made according to Example 14, herein-   MC=methyl ether cellulose-   mPDMS=mono-methacryloxypropyl terminated polydimethylsiloxane (MW    800-1000)-   Norbloc=2-(2′-hydroxy-5-methacrylyloxyethylphenyl)-2H-benzotriazole-   ppm=parts per million micrograms of sample per gram of dry lens-   PVP=polyvinylpyrrolidinone (K 90)-   Simma 2=3-methacryloxy-2-hydroxypropyloxy)propylbis    (trimethylsiloxy)methylsilane-   BBPS=borate buffered packaging solution-   SSPS=borate buffered sodium sulfate packaging solution-   TEGDMA=tetraethyleneglycol dimethacrylate-   w/w=weight/total weight-   w/v=weight/total volume-   v/v=volume/total volume

The following solutions were prepared for use

Borate Buffered Packaging Solution (BBPS)

A solution was made by adding 0.185 weight % of sodium borate, 0.926weight % boric acid and 98.89 weight % water into a volumetric flask andwas mixed at ambient temperature until all solids were dissolved.Properties for the BBPS are listed in Table 1, below.

Borate Buffered Saline Solution (BBSS)

A solution was made by adding 0.185 g of sodium borate, 0.926 g boricacid, 0.847 g sodium chloride and 100 mL water into a flask and wasmixed at ambient temperature until all solids were dissolved. Propertiesfor the BBSS are listed in Table 1, below

Borate Buffered Sodium Sulfate Packaging Solution (SSPS)

A solution was made by adding 0.185 weight % of sodium borate, 0.926weight % boric acid, 1.4 weight % of sodium sulfate and 97.49 weight %water into a volumetric flask and was mixed at ambient temperature untilall solids were dissolved. Properties for the SSPS are listed in Table1, below.

Borate Buffered Packaging Solution with 400 uL of Packing Soln. (spiked)

A solution was made by adding 0.15 weight % of sodium borate, 0.92weight % boric acid, 0.35% sodium chloride, 0.004% EDTA and 98.58 weight% water into a volumetric flask and was mixed at ambient temperatureuntil all solids were dissolved. Properties for the special packingsolution are listed in Table 1. below.

TABLE 1 Solution Properties Properties BBPS BBSS SSPS Spiked PH 7.59 (0)7.52 7.52 (0) 7.50 (0) Osmolality 163 (0) 417 382 (0.5) 273 (0)(mOsm/kg) (std) Conductivity 0.7 (0) 14.6 15.3 (0.2) 6.8 (0) (m S/cm)Ksp (Ag/solu- (Ag₂B₄O₇) 1.77 × 10⁻¹⁰ 1.2 × 10⁻⁵ 1.77 × 10⁻¹⁰ tion anion)(AgCl) (AgSO₄) (AgCl)

Example 1

A monomer mix is made by mixing 77 weight % of the monomers listed inTable 2 with and 23% D3O.

TABLE 2 Component Wt % SiMAA2 28 MPDMS 31 DMA 24 HEMA 6 PVP 7 Norbloc 2Blue HEMA 0.02 CGI 1850 0.48 TEGDMA 1.5

Contact lenses were made by placing the monomer mix into thermoplasticcontact lens molds, and irradiating using Philips TL20W/03T fluorescentbulbs (intensity of about 1 mW/cm² for 8 minutes and about 4 mW/cm² for4 minutes) at 45° C. The molds were opened and lenses were extractedinto IPA solvent to insure removal of residual diluent and monomers. Thelenses were then rinsed in a 50 ppm methyl cellulose in DI mixture toinsure removal of solvent. The lenses were then equilibrated indeionized water.

Examples 2-13

Lenses made as in Example 1 were placed in a 300 ppm sodium iodidesolution overnight at room temperature. The lenses were immersed in a150 ppm silver nitrate solution for 2-minutes at room temperature andthen rinsed 2-times with DI water in 30-minute intervals to remove anyexcess silver. Three lenses were equilibrated in each of the solutionslisted in Table 3, below. Each set of three contact lenses was packagedinto three polypropylene blister packs containing the solutions shown inTable 3. The blister packs were heat sealed (225° C., 90 psi and 1.5seconds). The blister packs containing the lenses were autoclaved at121° C. for 30 minutes, and allowed to cool to room temperature. Thenumber of autoclave cycles each set of blister packs was exposed to islisted in Table 3. Each lens was analyzed for residual silver contentafter the noted number of autoclave cycles. The results are shown inTable 3, below.

TABLE 3 Ex. # Solution # cycles [Ag] (μg)* 2 BBPS 1 4.37 (0.11) 3 BBPS 34.52 (0.06) 4 BBPS 5 4.57 (0.22) 5 BBPS 8 4.57 (0.07) 6 SSPS 1 3.3 (0.2)7 SSPS 3 3.4 (0.3) 8 SSPS 5 3.4 (0.1) 9 SSPS 8 3.4 (0.2) 10 Spiked 1 3.3(0.1) 11 Spiked 3 2.4 (0.1) 12 Spiked 5 1.9 (0.9) 13 Spiked 8 1.7 (0.1)*standard deviations shown in parenthesis

Example 14

The following ingredients were combined using the steps below togenerate Macromer.

TABLE 4 Weight (g) or Chemical volume (ml)Bis(dimethylamino)-methylsilane 5.72 g 1.0M Solution oftetrabutylammonium 3- 2.6 ml chlorobenzoate (TBACB) in THF p-xylene15.83 g MMA 29.44 g Bloc-HEMA 361.16 g THF 840 g Methyltrimethylsilyldimethylketene acetal 38.53 g 0.4M solution of tetrabutylammonium 3- 6ml chlorobenzoate (TBACB) in THF Step 2 Bloc-HEMA 89.23 g MPDMS 693.00 gTRIS 701.46 g Bis(dimethylamino)-methylsilane 3.81 g Step 3 Solution ofBloc-HEMA 361.16 g MMA 29.44 g Bis(dimethylamino)-methylsilane 1.92 gTHF 270 g Step 4 Water 93.9 g Methanol 141.2 g Dichloroacetic acid 1.68g Step 5 3-Isopropenyl-α,α-dimethylbenzyl isocyanate 169.07 g TEA 1.18 gBloc-HEMA, MMA, mPDMS (about 800 to about 1000 MW), TRIS, p-xylene andtetrahydrofuran (THF) were dried over preactivated 4A molecular sieve,and THF, mPDMS, and TRIS were passed through aluminum oxide columnbefore use.

To a dry container in a dry box under nitrogen was addedbis(dimethylamino)-methylsilane, a 1M solution of tetrabutylammonium3-chlorobenzoate (TBACB) in THF, p-xylene, MMA (1.4 eqv. relative toinitiator), Bloc-HEMA (8.5 eqv. relative to photoinitiator) and THF. Theabove mixture was charged to a dry flask equipped with a thermocoupleand a condenser connected to a nitrogen source.

To the reaction mixture was injected methyltrimethylsilyl dimethylketeneacetal while stirring and purging with nitrogen. The reaction wasallowed to exotherm to about 65° C. and then after the temperature ofthe solution dropped, a solution of TBACB in dry THF (0.4 M) was fed inslowly throughout the rest of the reaction. Then in step 2, a mixture ofBloc-HEMA (2.1 eqv. to initiator), mPDMS (3.3 eqv. to initiator), TRIS(7.9 eqv. to initiator) and bis(dimethylamino)-methylsilane, prepared indry box, was added under nitrogen.

The reaction mixture was again allowed to exotherm to approximately 42°C. and then allowed to cool to 32° C. The solution was stirred at 32° C.by using a temperature controller and heating equipment for about fivehours. In step 3, a mixture on of Bloc-HEMA (8.5 eqv. to initiator), MMA(1.4 eqv. relative to initiator) and bis(dimethylamino)-methylsilane wasadded and the whole mixture allowed to exotherm to 46-49° C. After themixture reacted about two hours, 270 g of THF was added to reduce theviscosity and the solution was stirred for additional 30 minutes.

In step 4, a mixture of water, methanol and dichloroacetic acid wasadded and the mixture was refluxed for five hours to de-block theprotecting groups. The solvents were then removed by distillation andtoluene was added to aid in removal of residual water until a vaportemperature reached 110° C.

A solution of TMI and 1.2 mole % TEA relative to TMI was added to theabove solution in toluene. The whole mixture was stirred at 110° C. forthree hours and the disappearance of the isocyanate peak was monitoredby IR. The toluene was removed under reduced pressure at around 45° C.to give a raw macromer.

Purification procedures were employed to remove high molecular weightspecies. The raw macromer was re-dissolved in acetone (2:1 w/w acetoneto macromer) and the acetone solution was set overnight to allow highmolecular weight species to separate. The top clear phase was filteredthrough a PTFE membrane by pressure filtration. The filtrate was slowlycharged into water (4:1 v/v water to filtrate) and the macromer wasprecipitated out. The macromer was collected and dried using a vacuumoven at 45-65° C. under reduced pressure until there was no weightchange.

Further purification to remove low molecular weight species was alsodone by re-precipitation of the Macromer from the mixture of acetone andacetonitrile (1:5 v/v).

Example 15

Sodium Iodide (3.2 mg Aldrich) was added to 15.0 g of a hydrogel blendmade from the following (all amounts were calculated as weight percentof the total weight of the combination): 17.98% Macromer 5, 28.0% mPDMS,14.0% TRIS, 26.0% DMA, 5.0% HEMA, 1.0% TEGDMA, 5.0% PVP, 2.0%Norbloc,1.0% CGI 1850 and 0.02% Blue HEMA, 80 weight percent of thepreceding component mixture was further diluted with diluent, 20 weightpercent of D3O (“D3O Monomer Blend”). The mixture was sonicated for 1.5hours at 30° C., and then stored in a heated oven @ 55° C. overnight.The monomer mix was degassed under vacuum for 30 minutes, and used tomake lenses, utilizing Topas frames at 50-55° C. under Philips TL03lamps with 30 minutes of irradiation.

Eight frames were manually demolded, and the lenses (obtained stickingto the back curve or front curve) were enclosed individually inhydration vehicles (Fisher brand, HistoPrep disposable plastic tissuecapsules) and immersed in 2 L of DI water containing 447 mg AgNO₃. Anorbital shaker was used to keep the solution agitated. After 2 hours,the lenses were removed from the hydration vehicles, and released fromthe molds in a jar containing 150 mL of silver nitrate solution (0.15mg/mL in DI water) and 225 mL isopropyl alcohol. After 2 hours, thesolution was replaced with 200 mL isopropanol, and the lenses were thenstepped down using DI water/IPA mixtures by (4×40 mL) exchanges of thehydration solution with DI water, allowing the lenses to equilibrate20-30 minutes between exchanges. The lenses were then transferred intoDI water for a total of 4×75 mL washes of 20-30 minutes each. Lensesfrom the last DI water wash were stored in a 10 mL of fresh DI water.The lenses were autoclaved (each in 3.0 mL of Special Packing Solution).The final silver content in the lenses was determined by INAA to be286±15 ppm (theoretical=189 ppm).

Example 16

Tetrabutylammonium Chloride (8.9 mg, Fluka) was added to 15.1 g of D3OMonomer Blend. The mixture was sonicated for 1 hour, rolled on a jarroller for a further 30 minutes, and then stored in a heated oven @ 55°C. overnight. The monomer mix was degassed under vacuum for 30 minutes,and used to make lenses, utilizing Topas frames at 50° C. under PhilipsTL03 lamps with 30 minutes of irradiation.

Ten frames of lenses were manually demolded, and the rings due to excessmonomer were discarded. The lenses, obtained sticking to either the backcurve or front curve, were loaded onto hydration trays, which were thenimmersed in 2.75 L of silver nitrate solution (‘silverizing bath’, 0.155mg/mL in DI water). The silver nitrate solution was kept agitated byutilizing an orbital shaker. After 2 hours, the lenses were removed fromthe hydration trays, and placed in a jar containing 120 mL solution fromthe ‘silverizing bath’ and 180 mL isopropanol to release the lenses fromthe molds.

The released lenses were then further hydrated analogously to theprocedure described in Example 15. The final silver content in thelenses was determined to be 331±7 ppm (theoretical=286 ppm). The averagehaze value for these lenses was 21.8±1.8% relative to CSI commercialstandards.

Examples 17-20

Lenses made in Examples 14 and 15 were packaged in 3.0 mL glass vialshalf of the lenses of each lens type were packaged in BBPS and the otherhalf were packaged in BBSS and sealed. The lenses were autoclaved one tothree times at 121° C. for 30 minutes. The lenses were evaluated forsilver content and the data is presented in Table 5, below.

TABLE 5 17 18 19 20 Antimicrobial AgCl AgCl AgI AgI salt Ksp - 1.77 ×10⁻¹⁰ 1.77 × 10⁻¹⁰ 8.52 × 10⁻¹⁷ 8.52 × 10⁻¹⁷ Antimicrobial salt SolutionBBPS BBSS BBPS BBSS [Ag]_(initial) 342 (6) 342 (6)   286 (15) 286 (15)[Ag]_(1 cycle) 180 (8) 42 (5) 233 (3) 131 (4)  [Ag]_(2 cycle) 164 (9) 36(3) 236 (6) 94 (6) [Ag]_(3 cycle)  179 (11) 33 (6) 239 (7) 62 (4) Valuesin parentheses are standard deviations

1-3. (canceled)
 4. The method of claim 19 wherein said packagingsolution salts has an osmolality of about 230 mOsm/kg or greater.
 5. Themethod of claim 19 wherein said packaging solution has a conductivity ofat least about 4 mS/cm or greater.
 6. The method of claim 19 whereinsaid packaging solution has a conductivity of at least about 5 mS/cm orgreater
 7. The method of claim 19 wherein said ophthalmic device is acontact lens.
 8. The packaging solution method of claim 19 wherein saidantimicrobial metal salt comprises at least one cation selected from thegroup consisting of Al⁺³, Co⁺², Co⁺³, Ca⁺², Mg⁺², Ni⁺², Ti⁺², Ti⁺³,Ti⁺⁴, V⁺², V⁺³, V⁺⁵, Sr⁺², Fe⁺², Fe⁺³, Ag⁺², Ag⁺, Au⁺², Au⁺³, Au⁺¹,Pd⁺², Pd⁺⁴, Pt⁺², Pt⁺⁴, Cu⁺¹, Cu⁺², Mn⁺², Mn⁺³, Mn⁺⁴, Zn⁺² andcombinations thereof.
 9. The method of claim 19 wherein saidantimicrobial metal salt comprises at least one cation selected from thegroup consisting of Mg⁺², Zn⁺², Cu⁺¹, Cu⁺², Au⁺², Au⁺³, Au⁺¹, Pd⁺²,Pd⁺⁴, Pt⁺², Pt⁺⁴, Ag⁺², Ag⁺¹ and combinations thereof.
 10. method ofclaim 19 wherein said antimicrobial metal salt is a silver salt. 11.(canceled)
 12. (canceled)
 13. (canceled)
 14. The method of claim 19wherein said ophthalmic device loses less than about 20% by weight ofthe antimicrobial salt during autoclaving and storing. 15-16. (canceled)17. (canceled)
 18. (canceled)
 19. A method for reducing loss of anantimicrobial metal from an ophthalmic lens comprising at least oneantimicrobial metal salt having a K_(sp) packaged in a packagingsolution comprising the step of packaging said ophthalmic lens in apackaging solution having an osmolality of about 220 mOsm/kg or greaterwhich is substantially free from packaging solution salts which haveanions which when combined with cations from said antimicrobial metalform a salt having a K_(sp) between the Ksp of said antimicrobial metalsalt and about 10⁻⁶.
 20. The method of claim 19 wherein said solution isa borate buffered solution comprising at least one packing solution saltselected from the group consisting of sodium sulfate, sodium lactate,sodium citrate, sodium chloride and mixtures thereof.
 21. An articlecomprising (a) an ophthalmic device comprising at least oneantimicrobial metal salt having a K_(sp) of less than about 10⁻¹⁰ (b)stored in a packaging solution having an osmolality of about 220 mOsm/kgor greater and comprising only packaging solution salts which, uponautoclaving and storage of said ophthalmic device in said packagingsolution, result in said ophthalmic device losing less than about 30% byweight of said antimicrobial metal salt.
 22. A solution for packaging anophthalmic device comprising at least one antimicrobial metal salthaving a K_(sp) wherein said solution has an osmolality of about 220mOsm/kg or greater and comprises packaging solution salts, wherein saidpackaging solution salts have at least one anion which when combinedwith a cation from said antimicrobial metal salt forms a second salthaving a K_(sp) which is at least about six orders of magnitude greaterthan said K_(sp) of said antimicrobial metal salt.